BioMed Central Page 1 of 11 (page number not for citation purposes) Journal of Occupational Medicine and Toxicology Open Access Research Cancer risk among residents of Rhineland-Palatinate winegrowing communities: a cancer-registry based ecological study Andreas Seidler 1,2,4 , Gaël Paul Hammer* 2,4 , Gabriele Husmann 4 , Jochem König 2 , Anne Krtschil 3 , Irene Schmidtmann 2 and Maria Blettner 2 Address: 1 Federal Institute for Occupational Safety and Health (BAuA), Berlin, Germany, 2 Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), Johannes Gutenberg-University Mainz, Germany, 3 Cancer Registry of Rhineland-Palatinate, Notification Office, Mainz, Germany and 4 Cancer Registry of Rhineland-Palatinate, Registration Office, Mainz, Germany Email: Andreas Seidler - seidler.andreas@baua.bund.de; Gaël Paul Hammer* - hammer@imbei.uni-mainz.de; Gabriele Husmann - husmann@imbei.uni-mainz.de; Jochem König - koenig@imbei.uni-mainz.de; Anne Krtschil - krtschil@uni-mainz.de; Irene Schmidtmann - schmidtmann@imbei.uni-mainz.de; Maria Blettner - blettner@imbei.uni-mainz.de * Corresponding author Abstract Aim: To investigate the cancer risk among residents of Rhineland-Palatinate winegrowing communities in an ecological study. Methods: On the basis of the Rhineland-Palatinate cancer-registry, we calculated age-adjusted incidence rate ratios for communities with a medium area under wine cultivation (>5 to 20 percent) and a large area under wine cultivation (>20 percent) in comparison with communities with a small area under wine cultivation (>0 to 5 percent). In a side analysis, standardized cancer incidence ratios (SIR) were computed separately for winegrowing communities with small, medium and large area under wine cultivation using estimated German incidence rates as reference. Results: A statistically significant positive association with the extent of viniculture can be observed for non-melanoma skin cancer in both males and females, and additionally for prostate cancer, bladder cancer, and non-Hodgkin lymphoma in males, but not in females. Lung cancer risk is significantly reduced in communities with a large area under cultivation. In the side-analysis, elevated SIR for endocrine-related tumors of the breast, testis, prostate, and endometrium were observed. Conclusion: This study points to a potentially increased risk of skin cancer, bladder cancer, and endocrine-mediated tumors in Rhineland-Palatinate winegrowing communities. However, due to the explorative ecologic study design and the problem of multiple testing, these findings are not conclusve for a causal relationship. Introduction Some previous studies point to a potential association between pesticide exposure resp. farming or winegrowing and lymphoma [1-5] or multiple myeloma [6-11], brain cancer [12-14], prostate cancer [15], or bladder cancer [16,17]. However, the mechanisms of the suspected carci- nogenic effects of pesticides are widely unclear. Published: 6 June 2008 Journal of Occupational Medicine and Toxicology 2008, 3:12 doi:10.1186/1745-6673-3-12 Received: 30 January 2008 Accepted: 6 June 2008 This article is available from: http://www.occup-med.com/content/3/1/12 © 2008 Seidler et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Journal of Occupational Medicine and Toxicology 2008, 3:12 http://www.occup-med.com/content/3/1/12 Page 2 of 11 (page number not for citation purposes) Among the hypothesis on potential carcinogenic mecha- nisms from pesticides, the endocrine mediated effects have received much attention. Several pesticides interact with endocrine receptors in vitro or have endocrine-medi- ated effects in laboratory animals in vivo: The European Union has listed over 40 pesticides suspected to interfere with the hormone system of humans and wildlife [18]. As endocrine-related mechanisms play an etiologic role in several cancers in humans, the potential association between exposure to pesticides with endocrine activity and cancer incidence has been discussed in the last years. Many epidemiological studies have, for example, exam- ined the relationship between pesticides and breast cancer [19]. However, although endogenous and exogenous estrogens are known to play a causal role in the aetiology of breast cancer, the to date epidemiological and experi- mental evidence is not conclusive for an association between exposure to organochlorine pesticides and breast cancer incidence (for an overview, see [19]). According to Barlow [19], the evidence on other endocrine-related tumour sites (testes, prostate, endometrium) is too sparse to draw any conclusions concerning pesticides. Rhineland-Palatinate is the federal state with the most extensive winegrowing in Germany: About 3 percent of the Rhineland-Palatinate area is under wine cultivation. Therefore, a potential pesticide exposure of the residential population might be assumed. Actual deposit measure- ments in one Rhineland-Palatinate wine district (Moselle region) point to an ongoing insecticide (parathione) and herbicide (atrazine, simazine) exposure of the residential population [20]. Repeatedly, a suspected increase in can- cer incidence has been a subject of concern in the men- tioned region. The aim of the present ecological study is therefore to investigate the cancer risk among residents of Rhineland-Palatinate winegrowing communities com- pared to the cancer risk among residents of communities with a small area under wine cultivation. Materials and methods Study population and study area Each Rhineland-Palatinate winegrowing community (n = 503, out of 2,305 communities in Rhineland-Palatinate) was categorized according to the proportion of area under wine cultivation of the whole community area (small: >0 to 5 percent; medium: >5 to 20 percent; large: >20 percent area under wine cultivation; see Table 1) based on official data for 1996. 1.3 percent of the total area of communities with a small area under cultivation is area under wine, respectively, 12.5 percent of the total area of communities with a medium area under cultivation, and 31.4 percent of the total area of communities with a large area under cul- tivation. Table 1 gives some characteristics of the Rhine- land-Palatinate study region. Cancer registry data This study is based on cancer cases registered in the Rhine- land-Palatinate cancer registry which covers a population of approximately 4,000,000 persons. We included all malignant tumours plus benign brain and CNS tumours and brain and CNS tumours of uncertain behaviour. Fur- thermore, we included malignant bladder tumours plus carcinoma in situ and tumours of uncertain behaviour of the bladder. Since January 2000 all Rhineland-Palatinate physicians and dentists are legally obliged to report inci- dent cancer cases to the cancer registry. Therefore, all above mentioned cancers diagnosed between 2000 and 2003 and reported until mid-2005 were included. The fol- lowing items are registered: diagnosis (ICD-10); topogra- phy and morphology (ICD-O-2); staging (TNM); incidence date; most valid basis of diagnosis; occasion of first detection; initial treatment; last occupation and long- est held occupation; and date and cause of death (where appropriate). Population figures and data on area under wine cultivation were obtained from the statistical office of Rhineland-Palatinate. Statistical methods Completeness of the Rhineland-Palatinate cancer registry varies with time, region, physician's specialization and type of cancer. This had to be considered in our analysis. Completeness is estimated by the ratio of reported cases to estimated cases for Rhineland-Palatinate calculated from a national pooling of cancer registry data [21,22]. In com- munities with a small area under wine cultivation, the completeness (excluding non-melanotic skin cancer) is Table 1: Characteristics of the Rhineland-Palatinate vineyard area Rhineland-Palatinate* Area under wine (% of community area) Total > 0%, ≤ 5% >5%, ≤ 20% >20% Communities 2,305 162 171 170 Total area (ha) 1,984,688 222,736 200,709 129,444 Area under wine (ha) 69,043 2,996 25,101 40,683 % area under wine 3.5% 1.3% 12.5% 31.4% Inhabitants (per ha) 4,000,567 (2.02) 564,210 (2.53) 526,486 (2.62) 301,193 (2.33) Inhabitants per community (median, min-max) 566 (6–184,752) 1,188 (72–99,750) 1,193 (95–80,535) 984 (84–40,110) * All data pertain to Dec 31st, 1996 (Statistisches Landesamt Rheinland-Pfalz 2006) Journal of Occupational Medicine and Toxicology 2008, 3:12 http://www.occup-med.com/content/3/1/12 Page 3 of 11 (page number not for citation purposes) Table 2: Cancer risks (incidence rate ratios RR) in men with residence in communities with a large or medium area under wine cultivation vs. men in communities with low area under wine cultivation Reference* (1,665,594 PY † ) Area under wine cultivation > 5, ≤ 20% of community area (1,039,435 PY † ) Area under wine cultivation > 20% of community area (612,714 PY † ) ICD-10 code Cases Cases RR ‡§ 95% CI Cases RR ‡§ 95% CI Head & neck (C00–C14) 369 188 0.91 0.72–1.15 94 0.86 0.65–1.14 Base of tongue (C01) 35 11 0.53 0.26–1.08 10 0.87 0.40–1.91 Other and unspecified parts of tongue (C02) 35 26 1.22 0.72–2.07 13 1.12 0.56–2.25 Floor of mouth (C04) 42 25 0.98 0.57–1.70 11 0.70 0.34–1.47 Palate (C05) 22 15 1.24 0.62–2.49 5 0.88 0.31–2.54 Other and unspecified parts of mouth (C06) 18 8 0.71 0.29–1.73 3 0.45 0.12–1.71 Parotid gland (C07) 14 8 0.92 0.36–2.30 4 0.80 0.24–2.67 Tonsil (C09) 47 22 0.78 0.45–1.34 13 0.79 0.40–1.56 Oropharynx (C10) 35 15 0.78 0.39–1.57 5 0.48 0.17–1.34 Piriform sinus (C12) 20 10 0.90 0.41–2.02 8 1.67 0.66–4.25 Hypopharynx (C13) 56 27 0.76 0.46–1.26 17 0.88 0.48–1.62 Oesophagus (C15) 156 94 0.96 0.73–1.27 42 0.82 0.57–1.20 Stomach (C16) 241 166 1.06 0.86–1.31 92 1.03 0.79–1.34 Small intestine (C17) 24 14 0.92 0.45–1.86 2 0.21 0.05–0.95 Colon, sigmoid & rectum (C18–C21) 1188 806 1.07 0.95–1.21 460 1.10 0.96–1.26 Colon (C18) 723 473 1.04 0.91–1.20 268 1.06 0.90–1.25 Rectosigmoid junction (C19) 51 42 1.33 0.89–2.00 30 1.68 1.04–2.71 Rectum (C20) 397 284 1.13 0.94–1.35 157 1.10 0.89–1.37 Anus and anal canal (C21) 17 7 0.66 0.26–1.64 5 0.85 0.29–2.50 Liver and intrahepatic bile ducts (C22) 141 73 0.94 0.68–1.30 37 0.88 0.58–1.32 Gallbladder & biliary tract (C23–C24) 76 33 0.67 0.44–1.02 27 0.95 0.59–1.54 Gallbladder (C23) 17 7 0.58 0.23–1.46 7 0.96 0.36–2.53 Other and unspecified parts of biliary tract (C24) 59 26 0.70 0.43–1.13 20 0.95 0.55–1.65 Pancreas (C25) 162 99 1.03 0.78–1.36 51 0.96 0.68–1.37 Nasal cavity and middle ear (C30–C31) 18 9 0.73 0.32–1.67 4 0.51 0.16–1.62 Larynx (C32) 135 78 0.94 0.68–1.29 39 0.88 0.59–1.31 Trachea, bronus and lung (C33–C34) 1039 530 0.98 0.84–1.14 232 0.77 0.64–0.92 Bronchus and lung (C34) 1036 530 0.98 0.84–1.15 232 0.77 0.64–0.92 Bone and articular cartilage (C40–C41) 11 7 0.88 0.32–2.42 3 0.49 0.13–1.89 Skin, malignant melanoma (C43) 230 188 1.32 1.08–1.60 119 1.50 1.18–1.91 Skin, other malignant neoplasms (C44) 1990 1748 1.32 1.20–1.45 959 1.39 1.25–1.54 Mesothelioma (C45) 19 12 1.09 0.52–2.28 5 0.92 0.32–2.68 Other connective and soft tissue (C49) 32 35 1.65 1.00–2.70 9 0.68 0.31–1.48 Breast (C50) 14 9 1.02 0.43–2.39 3 0.60 0.16–2.25 Penis (C60) 20 15 1.17 0.56–2.44 6 0.71 0.26–1.93 Prostate (C61) 1857 1359 1.26 1.12–1.41 787 1.26 1.11–1.43 Testis (C62) 154 107 1.18 0.88–1.60 77 1.31 0.94–1.83 Urinary tract (C64-C66+C68) 330 206 1.03 0.85–1.26 107 0.96 0.75–1.23 Kidney, except renal pelvis (C64) 269 171 1.06 0.86–1.32 89 1.00 0.76–1.31 Ureter (C66) 30 7 0.35 0.15–0.80 7 0.58 0.24–1.39 Bladder (C67, D09.0, D41.4) 699 470 1.16 1.01–1.34 266 1.31 1.10–1.55 Eye and adnexa (C69) 15 8 1.02 0.43–2.43 3 0.88 0.23–3.37 Meninges (C70) 22 20 1.45 0.78–2.69 7 0.88 0.35–2.18 Brain, CNS, meninges (C70–C72, D32–33, D42– 43) 133 90 1.08 0.81–1.44 53 1.04 0.73–1.49 Brain (C71, D33, D43) 109 70 1.02 0.74–1.41 45 1.06 0.72–1.57 Thyroid gland (C73) 33 23 1.11 0.64–1.92 16 1.31 0.68–2.53 Hodgkin's disease (C81) 40 24 0.86 0.51–1.46 12 0.64 0.32–1.27 Follicular NHL (C82) 29 21 1.23 0.67–2.25 19 1.98 1.01–3.85 NHL (C82–C85) 197 130 1.12 0.88–1.42 81 1.29 0.96–1.73 Diffuse NHL (C83) 122 66 0.91 0.66–1.24 31 0.80 0.52–1.23 Peripheral and cutaneous T-cell lymphomas (C84) 10 6 0.94 0.33–2.68 8 2.19 0.75–6.37 Other and unspecified types of NHL (C85) 36 37 1.64 1.03–2.59 23 1.84 1.05–3.23 Multiple myeloma (C90) 63 36 0.93 0.60–1.44 21 0.92 0.53–1.59 Leukaemia (C91–C95) 204 113 0.89 0.69–1.15 61 0.84 0.61–1.16 Lymphoid leukaemia (C91) 116 56 0.74 0.53–1.05 28 0.65 0.41–1.02 Journal of Occupational Medicine and Toxicology 2008, 3:12 http://www.occup-med.com/content/3/1/12 Page 4 of 11 (page number not for citation purposes) about 80 percent in males and 79 percent in females. Con- cerning lymphohaematopoetic malignancies, the com- pleteness is considerably lower; in communities with a small area under cultivation, only 62 percent of Non- Hodgkin lymphoma (NHL) in males and 64 percent in females are reported to the registry. Primary "internal" analysis of incidence ratio ratios for communities with a medium or large area under cultivation in comparison with communities with a small area under cultivation To account for regional variations in completeness, in our primary analysis communities with a small area under wine cultivation served as reference. Provided that the completeness does not differ systematically between winegrowing communities with a large area under cultiva- tion and adjoining communities with a small area under cultivation, this allows to calculate valid incidence rate ratios by Poisson regression. Population figures are reported in five year age categories by the State Statistical Office; due to small numbers, the use of a categorized age variable would have caused numerical problems in the regression analysis. Instead, age was included as a continuous variable in the regres- sion analysis (mid-point of each age category). Many fac- tors, like sociodemographic, lifestyle and environmental factors, might considerably differ between large cities and villages/small cities. Cities with more than 100,000 inhabitants (Mainz, Ludwigshafen/Rhein, Koblenz, Kai- serslautern) were therefore excluded from the analysis. Furthermore, we adjusted for rural (<5,000 inhabitants) vs. urban (≥ 5,000 inhabitants) communities. The propor- tion of community area under fruit cultivation (another potential source of pesticides exposure) was included in the analyses as dichotomous confounder (<5 percent vs. ≥ 5 percent of community area). All analyses were preformed in SAS [23], stratified by gen- der and cancer type. The regression analysis includes can- cer rate as dependent variable, and age, wine growing area, rural/urban setting and fruit cultivation. All analyses were stratified by gender and diagnosis. The results of our ini- tial Poisson regression indicated a possible problem with overdispersion, which is partly due to heterogeneity between communities with respect to unobserved risk fac- tors. We therefore opted to assume a negative binomial distribution for the dependent variable, which allows to estimate a dispersion parameter k for the variance (vari- ance = expected value·(1+k·expected value)) and includes the Poisson distribution as a special case (k = 0). The negative binomial distribution emerges naturally if expected counts (Poisson parameters) vary among com- munities according to a gamma distribution. The interpre- tation of rate ratios stays the same as for Poisson regression. However, results do not substantially differ. For a few rare cancers, the ML fitting algorithm did not converge using the negative binomial distribution. In these cases, estimates from Poisson regression are reported. Side analysis of standardized incidence ratios (SIR) using German incidence rates as reference Even in communities with a small area under cultivation, cancer incidence might be elevated, potentially leading to an underestimation of rate ratios in communities with medium or large area under cultivation. In an additional analysis, we therefore calculated standardized incidence ratios (SIR) regardless of the incompleteness of the Rhine- land-Palatinate cancer registry. Standardized cancer inci- dence ratios were separately computed for winegrowing communities with small, medium, and large area under cultivation using estimated German incidence rates. The expected numbers of cancer (E) for the time period 2000– 2003 were compared with the observed numbers (O), cal- culating standardized incidence ratios (SIR) as the ratio between the observed and expected numbers. Exact 95%- confidence intervals (CI) based on the Poisson distribu- tion of O were calculated. Results of any analysis based on small numbers are diffi- cult to interpret. Therefore, only those results based on at least ten cases in the respective referent group and ten cases in both comparison groups combined are reported here. Results Tables 2 and 3 present incidence rate ratios (RR) for can- cer in males and females for winegrowing communities with medium (> 5 to ≤ 20 percent) and large (>20 per- Myeloid leukaemia (C92) 77 52 1.09 0.75–1.59 27 0.99 0.61–1.60 Primary site unspecified 128 83 0.99 0.75–1.30 43 0.88 0.61–1.28 All malignancies (excluding C44) 7761 5024 1.12 1.05–1.19 2765 1.10 1.03–1.18 All malignancies (including C44) 9751 6772 1.15 1.09–1.22 3724 1.16 1.09–1.23 * Winegrowing communities with >0, <= 5% area under wine cultivation † PY: Person-Years were approximated by population figures: the sum of population at the end of the year in the years under consideration. ‡ adjusted for age, rural or urban environment, and fruit cultivation § Poisson distribution of case counts assumed for: C45, C50, C70 Table 2: Cancer risks (incidence rate ratios RR) in men with residence in communities with a large or medium area under wine cultivation vs. men in communities with low area under wine cultivation (Continued) Journal of Occupational Medicine and Toxicology 2008, 3:12 http://www.occup-med.com/content/3/1/12 Page 5 of 11 (page number not for citation purposes) Table 3: Cancer risks (incidence rate ratios RR) in women with residence in communities with a large or medium area under wine cultivation vs. women in communities with low area under wine cultivation Reference* (1,778,184 PY † ) Area under wine cultivation > 5, ≤ 20% of community area (1,098,069 PY † ) Area under wine cultivation > 20% of community area (634,060 PY † ) ICD-10 code Cases Cases RR ‡§ 95% CI Cases RR ‡§ 95% CI Head & neck (C00–C14) 123 70 1.05 0.74–1.50 41 1.14 0.75–1.74 Other and unspecified parts of tongue (C02) 14 8 1.01 0.41–2.48 6 1.56 0.52–4.64 Oropharynx (C10) 19 6 0.53 0.20–1.39 5 0.81 0.28–2.39 Oesophagus (C15) 38 17 0.89 0.46–1.70 9 0.91 0.40–2.08 Stomach (C16) 197 147 1.27 1.01–1.60 61 1.07 0.79–1.47 Small intestine (C17) 24 17 1.17 0.64–2.15 8 1.04 0.45–2.40 Colon, sigmoid & rectum (C18–C21) 1122 733 1.04 0.92–1.17 346 0.94 0.81–1.09 Colon (C18) 734 509 1.11 0.97–1.28 214 0.90 0.75–1.08 Rectosigmoid junction (C19) 64 32 0.78 0.51–1.21 20 0.86 0.50–1.48 Rectum (C20) 301 180 0.95 0.78–1.17 108 1.06 0.83–1.35 Anus and anal canal (C21) 23 12 0.89 0.44–1.81 4 0.60 0.20–1.83 Liver and intrahepatic bile ducts (C22) 43 32 1.17 0.72–1.90 19 1.20 0.66–2.19 Gallbladder & biliary tract (C23–C24) 79 58 1.13 0.79–1.61 19 0.64 0.38–1.09 Gallbladder (C23) 39 38 1.44 0.89–2.33 10 0.64 0.30–1.34 Other and unspecified parts of biliary tract (C24) 40 20 0.78 0.46–1.34 9 0.63 0.29–1.34 Pancreas (C25) 158 85 0.97 0.72–1.29 40 0.93 0.64–1.37 Larynx (C32) 19 12 0.99 0.47–2.07 4 0.56 0.18–1.75 Trachea, bronus and lung (C33–C34) 342 168 0.99 0.77–1.27 94 1.19 0.88–1.59 Bronchus and lung (C34) 340 167 0.99 0.77–1.27 94 1.19 0.89–1.60 Skin, malignant melanoma (C43) 274 212 1.17 0.96–1.42 109 1.00 0.78–1.28 Skin, other malignant neoplasms (C44) 1710 1620 1.40 1.27–1.54 807 1.38 1.23–1.53 Retroperitoneum and peritoneum (C48) 10 9 1.72 0.65–4.53 4 1.93 0.53–7.02 Other connective and soft tissue (C49) 30 17 0.98 0.54–1.79 9 1.03 0.46–2.32 Breast (C50) 2525 1527 1.08 0.98–1.20 779 1.01 0.90–1.12 Vulva (C51) 63 36 0.98 0.64–1.50 22 1.23 0.72–2.10 Vagina (C52) 18 20 1.80 0.94–3.45 5 0.82 0.29–2.33 Cervix uteri (C53) 162 97 1.03 0.79–1.34 47 0.94 0.66–1.34 Corpus uteri, (C54–C55) 382 244 1.15 0.94–1.41 146 1.20 0.95–1.52 Corpus uteri (C54) 370 232 1.13 0.92–1.39 144 1.22 0.97–1.54 Uterus, part unspecified (C55) 12 12 1.58 0.70–3.59 2 0.46 0.10–2.17 Ovary and other unspecified female genital organs (C56–C57) 297 196 1.09 0.89–1.34 96 0.97 0.75–1.26 Ovary (C56) 284 183 1.07 0.86–1.32 93 0.99 0.76–1.28 Other and unspecified female genital organs (C57) 13 13 1.66 0.76–3.63 3 0.73 0.19–2.72 Urinary tract (C64-C66+C68) 208 136 1.10 0.86–1.40 73 1.04 0.77–1.40 Kidney, except renal pelvis (C64) 166 116 1.14 0.88–1.48 63 1.09 0.79–1.50 Renal pelvis (C65) 24 10 0.71 0.33–1.49 4 0.55 0.18–1.71 Ureter (C66) 16 10 1.02 0.45–2.29 4 0.75 0.23–2.44 Bladder (C67, D09.0, D41.4) 251 158 1.09 0.88–1.34 85 1.19 0.90–1.56 Brain, CNS, meninges (C70–C72, D32–33, D42–43) 167 105 1.11 0.84–1.46 62 1.25 0.89–1.75 Meninges (C70) 57 46 1.33 0.87–2.03 24 1.29 0.75–2.21 Brain (C71, D33, D43) 107 57 0.98 0.68–1.40 37 1.21 0.79–1.86 Thyroid gland (C73) 102 75 1.20 0.86–1.67 32 0.86 0.56–1.34 Hodgkin's disease (C81) 39 20 0.83 0.48–1.44 9 0.64 0.29–1.39 NHL (C82–C85) 220 114 0.93 0.72–1.21 52 0.78 0.56–1.09 Follicular NHL (C82) 50 18 0.58 0.34–1.01 5 0.29 0.11–0.76 Diffuse NHL (C83) 106 69 1.05 0.76–1.45 25 0.73 0.46–1.17 Other and unspecified types of NHL (C85) 56 24 0.71 0.43–1.14 19 1.07 0.61–1.89 Multiple myeloma (C90) 68 30 0.72 0.46–1.13 21 0.88 0.51–1.49 Leukaemia (C91–C95) 135 65 0.80 0.59–1.09 43 0.98 0.68–1.43 Lymphoid leukaemia (C91) 67 33 0.78 0.51–1.18 22 0.90 0.54–1.50 Myeloid leukaemia (C92) 60 32 0.90 0.59–1.37 16 0.92 0.51–1.66 Journal of Occupational Medicine and Toxicology 2008, 3:12 http://www.occup-med.com/content/3/1/12 Page 6 of 11 (page number not for citation purposes) cent) area under cultivation compared to communities with small (> 0 to ≤ 5 percent) area under cultivation. Sig- nificantly increased RR are observed for non-melanoma skin cancer (C44 ICD-10) among men (RR = 1.32 (95% confidence interval CI 1.20–1.45) for medium and RR = 1.39 (95% CI 1.25–1.54) for a large area under cultiva- tion) as well as among women (RR = 1.40 (95% CI 1.27– 1.54) for medium and RR = 1.38 (95% CI 1.23–1.53) for a large area under cultivation). Among men, the rate ratios for a large vs. a small area under cultivation are significantly elevated for the follow- ing malignancies: malignant melanoma (C43 ICD-10; RR = 1.50; 95% CI 1.18–1.91), prostate cancer (C61 ICD-10: RR = 1.26; 95% CI 1.11–1.43), bladder cancer (C67 ICD- 10; RR = 1.31; 95% CI 1.10–1.55), follicular NHL (C82 ICD-10; RR = 1.98; 95% CI 1.01–3.85) and other and unspecified types of NHL (C85 ICD-10; RR = 1.84; 95% CI 1.05–3.23). In contrast, we find significantly decreased rate ratios for follicular NHL among women (RR = 0.29 (95% CI 0.11–0.76) for a large vs. a small area under cul- tivation). Furthermore rate ratios are significantly decreased among men for lung cancer (C34 ICD-10; RR = 0.77; 95% CI 0.64–0.92 for a large vs. a small area under cultivation). Both men and women showed a slightly elevated RR for all malignancies for communities with medium (men: RR = 1.15; 95% CI 1.09–1.22; women: RR = 1.14; 95% CI 1.08–1.21) as well as with a large area under cultivation (men: RR = 1.16; 95% CI 1.09–1.23; women: RR = 1.10; 95% CI 1.04–1.17). When non-melanotic skin cancer was excluded, among men, risk ratios for all malignancies remained signifi- cantly elevated in communities with medium and a large area under cultivation; among women, solely rate ratios in communities with a medium area under cultivation retained significance. Tables 4 and 5 present standardized incidence ratios (SIR) for cancer in males and females for winegrowing commu- nities with small (>0 to ≤ 5 percent), medium (> 5 to ≤ 20 percent) and large (>20 percent) area under cultivation using estimated incidence of cancer in the national popu- lation of Germany as reference. As the incompleteness of Table 4: Cancer risks (standardized incidence ratios SIR) in men with residence in communities with planted winegrowing areas with the estimated incidence of cancer in the national population of Germany as reference Area under wine cultivation > 0, ≤ 5% of community area (1,665,594 PY † ) Area under wine cultivation > 5, ≤ 20% of community area (1,039,435 PY † ) Area under wine cultivation > 20% of community area (612,714 PY † ) ICD-10 code Observed Expected SIR 95% CI Observed Expected SIR 95% CI Observed Expected SIR 95% CI Head & neck (C00–C14) 369 238.00 1.13 1.01–1.25 188 205.94 0.91 0.79–1.05 94 117.54 0.80 0.65–0.98 Stomach (C16) 241 421.10 0.57 0.50–0.65 166 262.89 0.63 0.54–0.74 92 144.55 0.64 0.51–0.78 Colon, sigmoid & rectum (C18–C21) 1188 1445.33 0.82 0.78–0.87 806 906.16 0.89 0.83–0.95 460 497.93 0.92 0.84–1.01 Trachea, bronchus and lung (C33–C34) 1039 1376.19 0.75 0.71–0.80 530 865.12 0.61 0.56–0.67 232 478.60 0.48 0.42–0.55 Skin, malignant melanoma (C43) 230 257.40 0.89 0.78–1.02 188 160.19 1.17 1.01–1.35 119 91.08 1.31 1.08–1.56 Prostate (C61) 1857 1833.70 1.01 0.97–1.06 1359 1152.26 1.18 1.12–1.24 787 628.58 1.25 1.17–1.34 Testis (C62) 154 164.80 0.93 0.79–1.09 107 101.97 1.05 0.86–1.27 77 61.20 1.26 0.99–1.57 Urinary tract (C64- C66+C68) 330 392.87 0.84 0.75–0.94 206 247.03 0.83 0.72–0.96 107 137.47 0.78 0.64–0.94 Bladder (C67, D09.0, D41.4) 699 718.87 0.97 0.90–1.05 470 451.25 1.04 0.95–1.14 266 246.29 1.08 0.95–1.22 NHL (C82–C85) 197 255.32 0.77 0.67–0.89 130 160.18 0.81 0.68–0.96 81 90.11 0.90 0.71–1.12 Leukaemia (C91–C95) 204 253.60 0.80 0.70–0.92 113 158.75 0.71 0.59–0.86 61 89.49 0.68 0.52–0.88 All malignancies (excluding C44) 7761 8751.69 0.89 0.87–0.91 5024 5493.56 0.91 0.89–0.94 2765 3041.59 0.91 0.88–0.94 † PY: Person-Years were approximated by population figures: the sum of population at the end of the year in the years under consideration. Primary site unspecified 116 78 1.18 0.90–1.56 36 1.13 0.76–1.68 All malignancies (excluding C44) 7258 4508 1.09 1.03–1.17 2293 1.04 0.97–1.11 All malignancies (including C44) 8968 6128 1.14 1.08–1.21 3100 1.10 1.04–1.17 * Winegrowing communities with >0, <= 5% area under wine cultivation † PY: Person-Years were approximated by population figures: the sum of population at the end of the year in the years under consideration. ‡ adjusted for age, rural or urban environment, and fruit cultivation § Poisson distribution of case counts assumed for: C21, C52, C55, C57, C65, C81 Table 3: Cancer risks (incidence rate ratios RR) in women with residence in communities with a large or medium area under wine cultivation vs. women in communities with low area under wine cultivation (Continued) Journal of Occupational Medicine and Toxicology 2008, 3:12 http://www.occup-med.com/content/3/1/12 Page 7 of 11 (page number not for citation purposes) the Rhineland-Palatinate cancer registry would tend to result in potentially considerable underestimation, decreased SIR are not mentioned in the following (and should not be interpreted). The standardized incidence ratios of malignant melanoma remains statistically increased in men (SIR for a medium area under cultiva- tion = 1.17 (95% CI 1.01–1.35), SIR for a large area under cultivation = 1.31 (95% CI 1.08–1.56)). Furthermore, the SIR for prostate cancer remains statistically significant: the SIR is 1.18 (95% CI 1.12–1.24) for a medium area under cultivation and 1.25 (95% CI 1.17–1.34) for a large area under cultivation. The increased incidence of testicular cancer in communities with a large area under wine culti- vation is of borderline statistical significance (SIR = 1.26; 95% CI 0.99–1.57). Among women, we find an elevated SIR for endometrial cancer in communities with a large area under cultivation (SIR = 1.43; 95% CI 1.20–1.68). Breast cancer incidence is increased in communities with a medium area under cultivation (SIR = 1.07; 95% CI 1.02–1.12), but not in communities with a large area under cultivation (SIR = 0.99; 95% CI 0.92–1.06). Discussion In this ecological study, a statistically significant positive association with the extent of viniculture is observed for non-melanoma skin cancer in males and females, prostate cancer, bladder cancer, and non-Hodgkin lymphoma in males, but not in females. Lung cancer risk is significantly reduced in communities with a large area under cultiva- tion. Our main hypothesis that pesticides might play a role for the observed associations will be discussed for specific cancer types in the following. Specific tumours Non-melanotic skin cancer Several studies have shown that the lifetime cumulative sun exposure is responsible for the development of non- melanotic skin cancer (for an overview, see [24,25]). In ecologic studies, squamous cell carcinoma is related more strongly to latitude or measured ultraviolet radiation than is basal cell carcinoma. As more outdoor workers might be occupied in regions with extensive winegrowing, our find- ing of an increased non-melanotic skin cancer risk in winegrowing communities appears plausible. In fact, in communities with a large area under cultivation, 14.8 per- cent of male skin cancer patients (C44 ICD-10) with known occupation (as recorded in the cancer registry) had worked as an outdoor worker (farmer, winegrower, gar- dener, forestry worker or construction worker). In com- munities with medium and a small area under cultivation, this proportion is 12.2 percent and 7.5 percent, respec- tively. Comparably, the proportion of outdoor workers among female cancer skin cancer patients (C44 ICD-10) is 7.6 percent, 5.1 percent and 2.6 percent in communities with a large, medium and small area under cultivation, respectively. Previous arsenic exposure has to be consid- ered as an alternative explanation: arsenical pesticides were applied by Moselle wine growers [26] between 1920 and 1942. The clinical signs of arsenic exposure are arseni- cal keratoses, which may progress to squamous cell carci- Table 5: Cancer risks (standardized incidence ratios SIR) in women with residence in communities with planted winegrowing areas with the estimated incidence of cancer in the national population of Germany as reference Area under wine cultivation > 0, ≤ 5% of community area (1,665,594 PY † ) Area under wine cultivation > 5, ≤ 20% of community area (1,039,435 PY † ) Area under wine cultivation > 20% of community area (612,714 PY † ) ICD-10 code Observed Expected SIR 95% CI Observed Expected SIR 95% CI Observed Expected SIR 95% CI Head & neck (C00–C14) 123 93.17 1.32 1.10–1.58 70 57.01 1.23 0.96–1.55 41 31.13 1.32 0.95–1.79 Stomach (C16) 197 302.45 0.65 0.56–0.75 147 183.37 0.80 0.68–0.94 61 96.98 0.63 0.48–0.81 Colon, sigmoid & rectum (C18–C21) 1122 1529.06 0.73 0.69–0.78 733 929.83 0.79 0.73–0.85 346 491.03 0.70 0.63–0.78 Trachea, bronchus and lung (C33–C34) 342 429.49 0.80 0.71–0.89 168 263.51 0.64 0.54–0.74 94 142.96 0.66 0.53–0.80 Skin, malignant melanoma (C43) 274 314.29 0.87 0.77–0.98 212 191.68 1.11 0.96–1.27 109 107.56 1.01 0.83–1.22 Breast (C50) 2525 2332.19 1.08 1.04–1.13 1527 1429.33 1.07 1.02–1.12 779 786.82 0.99 0.92–1.06 Cervix uteri (C53) 162 239.01 0.68 0.58–0.79 97 145.48 0.67 0.54–0.81 47 83.17 0.57 0.42–0.75 Corpus uteri, (C54–C55) 382 309.64 1.23 1.11–1.36 244 190.05 1.28 1.13–1.46 146 102.37 1.43 1.20–1.68 Ovary and other unspecified female genital organs (C56–C57) 297 449.08 0.66 0.59–0.74 196 273.91 0.72 0.62–0.82 96 149.12 0.64 0.52–0.79 Urinary tract (C64- C66+C68) 208 261.56 0.80 0.69–0.91 136 160.51 0.85 0.71–1.00 73 86.15 0.85 0.66–1.07 Bladder (C67, D09.0, D41.4) 251 325.54 0.77 0.68–0.87 158 200.30 0.79 0.67–0.92 85 107.82 0.79 0.63–0.97 NHL (C82–C85) 220 286.04 0.77 0.67–0.88 114 175.38 0.65 0.54–0.78 52 95.33 0.55 0.41–0.72 Leukaemia (C91–C95) 135 228.14 0.59 0.50–0.70 65 139.57 0.47 0.36–0.59 43 75.32 0.57 0.41–0.77 All malignancies (excluding C44) 7258 8285.78 0.88 0.86–0.90 4508 5070.41 0.89 0.86–0.92 2293 2740.00 0.84 0.80–0.87 † PY: Person-Years were approximated by population figures: the sum of population at the end of the year in the years under consideration. Journal of Occupational Medicine and Toxicology 2008, 3:12 http://www.occup-med.com/content/3/1/12 Page 8 of 11 (page number not for citation purposes) noma or basal cell carcinoma [27]. Moreover, arsenic seems to act as a co-carcinogen with ultraviolet radiation [27]. As the latency period of non-melanotic skin cancer is suspected to be very long, an excess in non-melanotic skin cancers might therefore be partly explained by arsenic exposure, however, this explanation appears rather specu- lative. Moreover, risk estimators for non-melanotic skin cancer do not markedly increase when our analysis is restricted to persons aged 70 or more. The association between sun exposure and melanoma of the skin seems to be more complex: Intermittent sun exposure and sunburn history rather than lifetime cumulative sun exposure plays a role in the aetiology of melanoma of the skin [28,29]. This complex relationship might explain why our study does not reveal a clearly increased melanoma incidence in communities with a large area under wine cultivation. Moreover, adjusting for potential confounders as, for example, leisure time UV exposure, was not possible in this study. Brain cancer While several epidemiological studies point to an increased brain cancer risk among pesticide exposed per- sons [13,14], few studies specifically focus on the residen- tial population in winegrowing regions. In their ecological study in the province of Trento, Italy, Ferrari and Lovaste [30] find the highest incidence rates of intrac- ranial tumours in regions of intensive fruit and wine cul- tivation. However, the authors do not indicate the significance level of their findings. Another ecological study among French agricultural workers reveals a signifi- cant association between pesticide exposure in vineyards and brain cancer mortality [31]. The results of our ecolog- ical study do not support an increased brain cancer risk of residents in winegrowing regions (RR in the primary anal- ysis for large vs. a small area under cultivation = 1.06 (95% CI 0.72–1.57) among men; RR = 1.21 (95% CI 0.79–1.86) among women). Rectum cancer Some previous studies point to a potentially elevated rec- tum cancer risk [32,33], other studies find reduced color- ectal cancer risks among farmers [34] or farm residents [35]. Altogether, there is very little evidence to date for a possible relationship between pesticide exposure and rec- tum cancer. Our finding of an increased cancer incidence of the rectosigmoid junction (but not of rectum cancer in all) among males living in winegrowing communities might be alternatively explained by life-style (e.g. dietary) or medical (participation at screening) factors, by inho- mogeneous reporting behavior, or by chance. Non-Hodgkin lymphoma The increased NHL incidence among male, but not among female inhabitants of communities with a medium or large area under wine cultivation suggests a potential occupational rather than residential aetiology. However, in communities with a medium or a large area under cultivation, only two male NHL patients (=2 per- cent of male NHL patients with known occupation, miss- ing values 55 percent) and one female NHL patient (=1.3 percent of female NHL patients with known occupation, missing values 44 percent) had worked as wine-growers, making an occupational aetiology improbable. Our finding of an increased NHL incidence among poten- tially pesticide-exposed residents of winegrowing commu- nities is in accordance with the literature. However, most previous studies are related to agricultural workers in gen- eral, not to winegrowing workers. In a large Italian multi- center case-control study [36], orchard, vineyard, and related tree and shrub workers appeared to be at increased risk for hematolymphopoietic malignancies. The carcino- genic effects of pesticides may be associated with their genotoxicity and immunotoxicity [37-39], increased cell proliferation [40], and association with chromosomal aberrations [41]. Because of the lack of a positive associa- tion between potential residential pesticide exposure and NHL in females (actually with a significantly decreased rate ratio for follicular NHL in winegrowing communities with a large area under cultivation), our study does not definitely support the hypothesis of an elevated NHL risk among the residential population in Rhineland-Palatinate winegrowing communities. Bladder cancer To date, there is inconclusive evidence for a relationship between pesticide exposure and bladder cancer. In a retro- spective cohort study among 32,600 employees of a lawn care company, Zahm [42] finds a significantly increased bladder cancer mortality. However, bladder cancer num- bers are very small; furthermore, two of the three observed deaths had no direct occupational contact with pesticides. Rusiecki et al. [16] evaluate the cancer incidence in atra- zine-exposed pesticide applicators among 53,943 partici- pants in the Agricultural Health Study. In their study, assessing atrazine exposure by lifetime days of exposure, the rate ratio for bladder cancer is non-significantly ele- vated to 3.06 (95% CI 0.86–10.81). Assessing atrazine exposure by intensity-weighted lifetime days, the rate ratio for bladder cancer decreases to 0.85 (95% CI 0.24– 2.94). Viel and Challier [17] analyze the mortality from bladder cancer among French farmers. While the mortal- ity among farmers is non-significantly lowered (standard- ized mortality ratio = 0.96; 95% CI 0.85–1.08), there is a significant association with exposure to pesticides in vine- yards (risk ratio = 1.14; 95% CI 1.07–1.22). According to the authors, these results could explain the French south- north gradient in bladder cancer, as vineyards are mainly located in Southern France. Journal of Occupational Medicine and Toxicology 2008, 3:12 http://www.occup-med.com/content/3/1/12 Page 9 of 11 (page number not for citation purposes) Prostate cancer Our finding of an increased prostate cancer risk in poten- tially pesticide-exposed residents of winegrowing commu- nities is in accordance with the literature. In a recently conducted meta-analysis, van Maele-Fabry et al. [15] include 18 epidemiological studies published between 1984 and 2004. The combined rate ratio for all studies is 1.28 (95% CI 1.05–1.58). According to the authors, no specific pesticide or chemical class is responsible for the increased risk; nevertheless, the strongest evidence con- sists for phenoxy herbicides possibly in relation with dioxin and furan contamination. Van Maele-Fabry [15] point to the lack of fundamental understanding of the basic biology of human prostate cancer: hormones (both androgens and estrogens) would likely play a role in the etiology or promotion of prostate cancer. Therefore, the authors regard it as plausible that chemicals able to mod- ulate steroid sex hormones as agonists, antagonists or as mixed agonist-antagonist might contribute to the devel- opment of prostate cancer through hormone-mediated effects. Several pesticides might interfere with sexual hor- mones through direct action on receptors but also through indirect non-receptorial mechanisms. Limitations We applied an ecologic study design which does not allow a differentiation between residential, occupational, and life-style risk factors for cancer. The chief limitation of eco- logic studies is the inability to link exposure with disease in particular individuals. A second major limitation of ecologic studies is the lack of ability to control for the effects of potential confounding factors. Thus, observed risk differences between communities with different area under cultivation may be due not to varying levels of pes- ticide usage, but rather to the independent effect of other confounding variables on cancer risk. Moreover, our "exposure" categories (small, medium, or large area under cultivation) represent very crude indicators of the individ- ual exposure; the actual individual exposure depends on occupation, place of residence at the time of pesticide spraying, wind direction etc. Furthermore, several tests were performed, introducing a multiple comparison problem (altogether, 270 risk ratios were calculated). In general, our study design should therefore be regarded as exploratory rather than hypothesis testing. Due to small numbers, particularly for cancer cases in communities with a large area under cultivation, the power of the study to detect slight increases in incidence is limited. Many other potential risk factors of occupation and lifestyle from living in agricultural area would need to be dis- cussed to explain the findings, but these would have to be collected in a study using individual information. For instance, data on socioeconomic levels or smoking preva- lence were not available on a small scale. The use of 1996 data on agricultural characteristics might be criticised, since a lag time of 4–7 years for cancers occurring 2000– 2003 is not plausible. It was not possible to obtain older data, but since the political boundaries did not change and agricultural land use stayed constant, their use seems warranted in the current study. The completeness of reported cancer cases is still relatively low in Rhineland-Palatinate (about 80 percent for all can- cers). Therefore, the calculation of standardized incidence ratios for residents of winegrowing communities in com- parison with the population of Rhineland-Palatinate might at least partly reflect a higher completeness rather than truly elevated risks. As a probably more reliable approach of calculating cancer risks, we therefore decided to compare the observed cancer cases in communities with a medium or a large area under cultivation with – as a kind of internal reference – the number of cases reported in communities with a small area under cultivation. While we regard the "internal" comparison of winegrowing communities (communities with a medium or large area versus small are under cultivation) as a more reliable approach than the comparison with the Rhineland-Palat- inate population, we nevertheless cannot totally exclude a higher (or lower) completeness in communities with a medium or large area under cultivation than in communi- ties with a small area under cultivation. Increased incidence of endocrine-related tumors with the estimated incidence of cancer in the national population of Germany as reference In our primary analysis, we compared cancer rates in com- munities with a large resp. medium area under cultivation with cancer rates in communities with a small area under cultivation. However, in fact even in communities with a small area under cultivation, cancer incidence might be elevated, potentially leading to an underestimation of the results of our primary analysis (concerning rate ratios in communities with medium or large area under cultiva- tion). In a side analysis, we therefore calculated standard- ized incidence ratios regardless of the incompleteness of the Rhineland-Palatinate cancer. Because of the incom- pleteness of the Rhineland-Palatinate cancer registry, the results of the calculation of standardized incidence ratios (SIR) tend to underestimate the true cancer risks for incompletely recorded cancer subentities; therefore decreased SIR should not be interpreted. If standardized incidence ratios were calculated with the estimated inci- dence of cancer in the national population of Germany as reference, among men we found an elevated SIR for pros- tate cancer and testicular cancer in communities with a large area under wine cultivation. Among women, we found an elevated SIR for endometrial cancer and (in communities with a medium area under cultivation, but not in communities with a large area under cultivation) for breast cancer incidence. Altogether, the results of our Journal of Occupational Medicine and Toxicology 2008, 3:12 http://www.occup-med.com/content/3/1/12 Page 10 of 11 (page number not for citation purposes) additional SIR analysis are compatible with a potential carcinogenic role of pesticides in the etiology of endo- crine-related tumors of the breast, testis, prostate, and endometrium. Conclusion This ecologic study is the first attempt to examine the rela- tionship between cancer incidence and the area under wine cultivation in Rhineland-Palatinate winegrowing communities. The study results point to a potentially ele- vated skin cancer risk, bladder cancer risk, and endocrine- related (prostate, testicular, breast, and endometrium) cancer risk of the population in communities with a large area under wine cultivation. Mainly due to the ecologic study design, the problem of multiple testing, and due to the insufficient completeness of the Rhineland-Palatinate cancer registry concerning the considered region, these findings are not conclusive for a causal relationship. There is a need for analytic epidemiologic studies differentiating between environmental and occupational exposures to further clarify the cancer risk associated with pesticide usage in wine cultivation. Competing interests The authors declare that they have no competing interests. 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Sir Paul Nurse, Cancer Research UK Your research papers will be: available free of charge to the entire biomedical community peer reviewed and published immediately upon acceptance cited in PubMed and archived on PubMed Central yours — you keep the copyright BioMedcentral Submit... Zahm SH, Blair A: Pesticides and non-Hodgkin's lymphoma Cancer Res 1992, 52(suppl):5485s-8s Figgs LW, Holland NT, Rothmann N, Zahm SH, Tarone RE, Hill R, Vogt RF, Smith MT, Boysen CD, Holmes FF, VanDyck K, Blair A: Increased lymphocyte replicative index following 2,4-dichlorophenoxyacetic acid herbicide exposure Cancer Causes Control 2000, 11:373-80 Schroeder JC, Olshan AF, Baric R, Dent GA, Weinberg... and published immediately upon acceptance cited in PubMed and archived on PubMed Central yours — you keep the copyright BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 11 of 11 (page number not for citation purposes) . Gutenberg-University Mainz, Germany, 3 Cancer Registry of Rhineland-Palatinate, Notification Office, Mainz, Germany and 4 Cancer Registry of Rhineland-Palatinate, Registration Office, Mainz, Germany Email: Andreas. residents of Rhineland-Palatinate winegrowing communities in an ecological study. Methods: On the basis of the Rhineland-Palatinate cancer- registry, we calculated age-adjusted incidence rate ratios. aim of the present ecological study is therefore to investigate the cancer risk among residents of Rhineland-Palatinate winegrowing communities com- pared to the cancer risk among residents of